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The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
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Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation
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Histone H4 promotes prothrombin autoactivation.

Sergio Barranco-Medina1, Nicola Pozzi, Austin D Vogt

  • 1From the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.

The Journal of Biological Chemistry
|November 2, 2013
PubMed
Summary
This summary is machine-generated.

Histone H4 binding triggers prothrombin autoactivation to thrombin under physiological conditions, independent of the coagulation cascade. This finding reveals a new mechanism for thrombin generation relevant to disease.

Keywords:
Blood Coagulation FactorsEnzyme MechanismsProtein ConformationProthrombinThrombin

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • Prothrombin (factor II) is a precursor to thrombin, a key enzyme in blood coagulation.
  • Prothrombin autoactivation, a spontaneous conversion to thrombin, is known to occur upon specific mutations exposing Arg-320.
  • The occurrence of prothrombin autoactivation in wild-type under physiological conditions remains largely unknown.

Purpose of the Study:

  • To investigate whether histone H4 can induce prothrombin autoactivation under physiological conditions.
  • To elucidate the mechanism and structural changes involved in histone H4-mediated prothrombin autoactivation.
  • To explore the pathophysiological relevance of this autoactivation pathway.

Main Methods:

  • Fluorescence titrations to assess histone H4 binding affinity to prothrombin.
  • Stopped-flow and luminescence resonance energy transfer (LRET) to study binding kinetics and conformational changes.
  • Site-directed mutagenesis to investigate the role of catalytic residues (Ser-525) and the Gla domain.

Main Results:

  • Histone H4 directly binds to prothrombin with high affinity (low nM range).
  • Histone H4 selectively binds to a collapsed prothrombin conformation, inducing a transition to a new state with altered inter-kringle distances.
  • This autoactivation is dependent on the catalytic Ser-525 and the Gla domain, and abrogated by mutations.

Conclusions:

  • Histone H4 binding induces prothrombin autoactivation to thrombin, a process independent of the classical coagulation cascade.
  • Prothrombin's conformational plasticity, influenced by its inter-kringle linker domain, dictates its functional state.
  • This histone H4-driven autoactivation pathway offers a novel mechanistic insight into the prothrombotic phenotype observed during cellular damage and histone release.